The long-term objective of this research is to understand the molecular and structural mechanisms of the function of transient receptor potential (TRP) channels. In particular, we will focus on the canonical TRP (TRPC) channels, which are present in blood vessels, heart, lung, kidney and brain and are involved in regulating diverse biological processes ranging from neural and cardiovascular functions to sexual behavior. The seven members of the TRPC channel family conduct calcium into cells and are in turn regulated by intracellular calcium. All TRPC proteins interact directly with calmodulin (CaM), a ubiquitous calcium sensing protein, which may mediate calcium-dependent feedback regulation of TRPC channel activity and function. Our specific aims are to solve the high-resolution crystal structure of the complex of CaM and each of the four putative CaM-binding sites in TRPC proteins and to study the molecular mechanism and functional impact of CaM binding to each site. Our central hypothesis is that CaM forms distinct interactions with each TRPC site and these interactions regulate channel properties and functions in a channel-specific fashion. Mutations in TRPC channels have been linked to focal and segmental glomerulosclerosis, a hereditary kidney disorder leading to renal failure, and the abundance of TRPC channels in airway smooth muscles and blood vesicles suggest that their malfunction could play a role in asthma, chronic obstructive pulmonary disease, hypertension and various types of cardiovascular diseases. Thus, our studies will not only provide a better understanding of the function and regulation of these biologically important ion channels but also facilitate the development of new therapeutic strategies for the treatment of a host of human diseases. PUBLIC HEALTH RELEVANCE: TRPC channels are found in blood vessels, heart, lung, kidney and brain and are involved in regulating numerous biological processes ranging from neural and cardiovascular functions to sexual behavior. Malfunction of these channels may cause human diseases such as asthma and various types of cardiovascular diseases. A better understanding of how these channels work may provide new ways to treat a host of human diseases.